The main objective of the proposed research is to develop a focused ultrasound (FUS) method to reversibly modulate (either elicit or suppress) neural activities of specific brain regions. We will develop a magnetic resonance imaging (MRI)-guided sonication environment, capable of evaluating local brain function using electrophysiological recordings (electroencephalography and electromyography) and real- time functional magnetic resonance imaging (rtfMRI). We will examine sonication parameters and their corresponding modulatory effects based on closed-loop monitoring of the electrophysiological data (EEG and EMG signal magnitude), supported by the level of the blood-oxygenation-level-dependent (BOLD) fMRI signal originating from the targeted brain tissue. Consequently, we will examine the range of sonication parameters which induce reversible suppression of regional cortical activity in the primary visual cortex and elicit excitation of activity in the sensorimotor cortex. The dose (duration)-dependent modulatory effects of FUS and their temporal dynamics will be probed via interleaved acquisition of fMRI and EEG/EMG using a trial-based paradigm design. To probe the safety of the method, immunohistological analysis examining biological effects of the sonication in terms of tissue or vascular damage will be performed at variable time points, covering acute, delayed, and long-term periods after the initial sonication. The ability to non-invasively modulate a specific brain area would enable the study of causal relations between brain activity and behavior, including the investigation of functional connectivity between brain regions. The success of this study will result in the exploration of novel potential therapeutic applications of FUS for numerous neurological and psychiatric disorders. PUBLIC HEALTH RELEVANCE: This study will explore the use of focused ultrasound sound waves to temporarily modulate the function of region-specific brain tissue in a non-invasive manner. The success of the proposed method will offer a diagnostic assessment of how well the different parts of the brain are functionally operated and connected to each other. Apart from its potential utility as a diagnostic tool, the ability to suppress or excite local brain tissue in a controlled manner also offers therapeutic potential in the treatment of various neurological and psychiatric disorders.